Rosacea is a highly prevalent, chronic inflammatory skin condition estimated to affect 16 million Americans.1-2 Rosacea is a common, chronic and progressive inflammatory disease with skin features characterized by blushing and flushing, facial erythema, papules, pustules, telangiectasia and sometimes ocular lesions known as ocular rosacea. In severe cases, particularly in men, rhinophyma, or a bulbous enlargement of the nose, may occur. Rosacea develops over the course of several years with periods of exacerbation triggered by various stimuli such as temperature changes, alcohol, spicy foods, sun exposure and emotional factors.
The prevalence of rosacea in the European population ranges between 0.09 and 22%, with a peak age of onset between 25 and 70 and is much more common in people with a light complexion. It more particularly affects women although the condition is generally more severe in men. The prevalence of family histories of rosacea has been reported.
Four subtypes of rosacea have been defined according to the degree of primary features, such as vasomotor flushing, persistent erythema, papules and pustules, telangiectasias (Wilkin J et al., JAAD, 2002, 46: 584-587). Erythematotelangiectatic rosacea (ETR) is mainly characterized by vasomotor flushing and persistent central facial erythema. Telangiectasias are commonly observed but are not essential for the diagnosis of this subtype. Central facial edema, burning or stinging sensations and rough, flaky skin are also symptoms that have sometimes been reported. A history of flushing as the only symptom is commonly found in people with erythematotelangiectatic rosacea.
Papulopustular rosacea (PPR) is characterized by persistent central facial erythema and transient crops of papules and/or pustules in the center of the face. However, the papules and pustules can also occur in periorificial regions, i.e., around the mouth, nose and eyes. The papulopustular subtype resembles acne vulgaris, but comedones are absent. Rosacea and acne may coexist in a same patient, in which case comedones may also be present alongside the papules and pustules suggestive of rosacea. People with papulopustular rosacea sometimes complain of a burning or stinging sensation. This subtype is often observed before or at the same time as ETR (including the presence of telangiectasias). The telangiectasias may be obscured by the persistent erythema and the papules and pustules, but they tend to become more visible after successful treatments that cover up these features. Papulopustular rosacea (PPR) is a subtype of the inflammatory lesions that is associated with great psychological distress.3 Facial blemishes have been found to significantly impair health-related quality of life, along with a fear of negative evaluation by others.4 Moreover, PPR is characterized by the presence of inflammatory infiltrates that accompany flares, along with a heightened immune response involving neutrophilic infiltration and increased gene expression of IL-8 (Steinhoff et al. J Investig Dermatol Symp Proc 2011; 15:2-11)
Phymatous rosacea is characterized by a thickening of the skin, irregular surface nodularities and swelling. The nose is most commonly affected but phymatous rosacea can also involve other areas such as the chin, the forehead, the cheeks and the ears. Patients with this subtype sometimes exhibit prominent, enlarged follicles in the affected areas as well as telangiectasias. This subtype often occurs before or at the same time as ETR or PPR (including the presence of persistent erythema, telangiectasias, papules and pustules). In the case of rhinophyma, these additional stigmata may be particularly pronounced in the nasal region.
Ocular rosacea (or ophthalmic rosacea) exhibits symptoms restricted to the ocular area with blepharitis, conjunctivitis and keratitis. The diagnosis of ocular rosacea should be considered when a patient presents with one or more of the following ocular signs and symptoms: watery or bloodshot eyes (interpalpebral conjunctival hyperemia), foreign body sensation, burning or stinging, dry or itchy eyes, sensitivity to light, blurred vision, conjunctival telangiectasias or eyelid margin telangiectasias or erythema of the eyelid and periocular area.
The pathogenesis of rosacea is not yet completely understood. Its etiology is multifactorial. In addition to exogenous factors (including UV light, heat and alcohol), it may be secondary to parasitic involvement (particularly Demodex folliculorum mites).5-6 Such factors activate neurovascular and/or immune responses, and consequently inflammatory cascades. Intermittent flares may contribute to the chronicity of rosacea as they are associated with prolonged vasodilation, perivascular inflammation, edema and exposure to cytokines and cellular infiltrates. Some studies of PPR observed higher mite densities compared to controls (Forton et al., Br J Dermatol 1993; 128(6):650-9; Karincaoglu et al., J Dermatol 2004; 31(8):618-26). Skin affected by rosacea is highly sensitive and prone to iffitation.7 
Management of rosacea is difficult and currently the most used therapies comprise oral antibiotics (tetracycline or its derivatives, metronidazole and macrolides) and oral retinoids. There are only a few current treatment options for inflammatory lesions of rosacea, and not many alternatives exist with high efficacy and once-daily dosing. A recent Cochrane review noted that it is unclear which is most effective, while some evidence supports the efficacy of topical metronidazole, azelaic acid and subantimicrobial-dose doxycycline in the treatment of moderate to severe rosacea.8 In a national survey of current rosacea medication users, 46% of patients had previously changed medications, usually due to a lack of improvement.9 Slow and incomplete treatment, and short period of relapse-free time have been noticed with some conventional treatments.
Ivermectin is an anti-parasitic drug derivative from the macrocyclic lactones family approved for human use for treatment and chemoprophylaxis of onchocerciasis and strongyloidiasis since 1996 in the USA and since 1988 in France. In addition, it has been in approved in France for the treatment of human scabies. Oral ivermectin in human and animal demodicidosis was effective in reducing Demodex folliculorum and improving demodicidosis. Moreover, when administered orally, ivermectin combined with a subsequent weekly application of topical permethrin showed treatment efficacy in a patient presenting chronic rosacea-like demodicidosis (14).
U.S. Pat. No. 5,952,372 discloses a method of treating rosacea in humans involving orally or topically administering ivermectin. However, according to U.S. Pat. No. 5,952,372, because of the skin barrier effect, topical treatment with ivermectin would be anticipated to require once- or twice-daily applications for as long as four weeks to achieve sufficient follicle penetration and effective miticidal activity. It further describes that after ivermectin carries out its miticidal activity on skin Demodex folliculorum organisms, inflammatory responses to them begin to diminish but remnants of the dead mites still elicit some flushing and lesion formation until the cleanup processes of the body remove them, a process that requires six to eight weeks. It suggests to employ conventional anti-rosacea medications, such as oral tetracycline and topical metronidazole, to suppress early flareups and to give early clinical response during the initial phase of ivermectin administration. U.S. Pat. No. 5,952,372 contains no specific disclosure on topical treatment of PPR.
U.S. Pat. No. 6,133,310 and U.S. Pat. No. 8,415,311 also disclose a method of treating acne rosacea by topical application of ivermectin. However, they contain no specific disclosure on treating inflammatory lesions of rosacea or PPR.
Accordingly, there is a need for an once-daily topical treatment of inflammatory lesions of rosacea with an earlier onset of significant effectiveness and a prolonged time to relapse than the currently available treatments, in order to provide safe, more rapid and longer lasting relief, and better patient compliance to those in need of such treatment. Such need is met by the present invention.